Objectiv To investigate an autosomal dominant non-syndromic hearing loss family pedigree com-prehensively,aiming to precisely define its clinical phenotypes and uncover the underlying molecular genetic etiolo-gy.Methods A detailed interrogation of the proband's medical history and family history was conducted.Physical examinations,audiological assessments and temporal bone CT scans were performed.Genomic DNA was extracted from the peripheral blood of the proband(Ⅳ-8)for whole-exome sequencing(WES).Subsequently,candidate vari-ants identified through WES were validated among family members using Sanger sequencing.Results There were 36 individuals in 4 generations in this family pedigree,showing autosomal dominant inheritance.Among them,16 individuals presented with progressive hearing loss.Audiological examinations were completed for 13 of them,re-vealing normal hearing in three individuals(Ⅲ-1,Ⅲ-1 1,Ⅳ-4)and bilateral symmetric hearing loss of varying se-verity in the remaining ten(Ⅱ-2,Ⅱ-4,Ⅱ-10,Ⅲ-4,Ⅲ-10,Ⅲ-13,Ⅲ-14,Ⅳ-1,Ⅳ-7,Ⅳ-8),and the degree of hearing loss was related to age.WES of Ⅳ-8 revealed that she carried the variant NM_199330.2(HOMER2):c.1064 A＞G(p.Ter354Trpext10),and Sanger sequencing verified the variation at this site.Peripheral blood samples of 18 individuals in this family were collected in total.All affected individuals(Ⅱ-2,Ⅱ-4,Ⅱ-10,Ⅲ-4,Ⅲ-9,Ⅲ-10,Ⅲ-13,Ⅲ-14,Ⅳ-1,Ⅳ-7,Ⅳ-8)carried the HOMER2 c.1064 A＞G variant,except for one young member(Ⅳ-6)who had not yet developed hearing loss.Unaffected individuals(Ⅱ-5,Ⅲ-1,Ⅲ-5,Ⅲ-11,Ⅳ-2,Ⅳ-4)lacked the variant,demonstrating complete cosegregation of genotype and phenotype.According to ACMG guide-lines,this variant was classified as likely pathogenic(PM2+PP1+PM4).Conclusion The c.1064 A＞G(p.Ter354Trpext10)variant of the HOMER2 gene is the molecular genetic etiology of this hereditary deafness family pedigree.

Secondary osteoporosis is common in patients with early breast cancer, manifesting as low back pain, bone and joint symptoms, and osteoporotic fractures. Bisphosphonate and denosumab can reduce the incidence of fractures by minimizing bone loss, though they differ in efficacy, treatment course, and side effects. Patients should consider the pros and cons when selecting a drug. Recent studies also focus on decreasing the incidence of bone metastases. This article reviews recent advancements in the use of these two drugs for managing bone health in early breast cancer.

"Weibing" is a fundamental concept in traditional Chinese medicine (TCM), representing a transitional state characterized by diminished self-regulatory abilities without overt physiological or social dysfunction. This perspective delves into the biological foundations and quantifiable markers of Weibing, aiming to establish a research framework for early disease intervention. Here, we propose the "Health Quadrant Classification" system, which divides the state of human body into health, sub-health, disease-susceptible state, and disease. We suggest the disease-susceptible stage emerges as a pivotal point for TCM interventions. To understand the intrinsic dynamics of this state, we propose laboratory and clinical studies utilizing time-series experiments and stress-induced disease susceptibility models. At the molecular level, bio-omics technologies and bioinformatics approaches are highlighted for uncovering intricate changes during disease progression. Furthermore, we discuss the application of mathematical models and artificial intelligence in developing early warning systems to anticipate and avert the transition from health to disease. This approach resonates with TCM's preventive philosophy, emphasizing proactive health maintenance and disease prevention. Ultimately, our perspective underscores the significance of integrating modern scientific methodologies with TCM principles to propel Weibing research and early intervention strategies forward.

Objective:To prepare ((2-(2-chlorophenyl)-3-(4-((2- 18F-fluoroethyl)oxy)phenyl)-5, 6, 7, 8-tetrahydrooxepino[3, 2-c]pyrazol-8-yl)amino)methanoic acid methyl ester ( 18F-JR-1001) and evaluate its binding affinity to the cannabinoid type 1 receptor (CB1R). Methods:18F-JR-1001 was synthesized using an integrated automated synthesis module, and its radiochemical yield (RCY) and molar activity were determined. Cell-specific uptake, lipid-water partition coefficient (log P), competitive binding assays, and in vitro stability tests were performed. Rimonabant-fed rat models (blocking group) with pre-occupied CB1R were established. Radioautography and microPET/CT imaging were conducted on both the blocking group and normal Sprague-Dawley (SD) rats to evaluate the brain uptake of 18F-JR-1001 and its blood-brain barrier (BBB) penetration capability. Results:The RCY of the synthetic 18F-JR-1001 after decay correction was (32.5±9.2)% ( n=10), with the molar activity of (194.6±67.3)GBq/μmol. Cell experiments demonstrated that 18F-JR-1001 exhibited specificity for CB1R, with log P of 3.40±0.11 ( n=3) and half-maximal inhibitory concentration of 0.975nmol/L. Within 3h at 37℃, the radiochemical purity of 18F-JR-1001 in physiological saline and blood remained above 92%, with no significant radioactive by-product peaks observed. Radioautography showed that the whole brain uptake of 18F-JR-1001 in the blocking group was 65.6% of that in normal SD rats. MicroPET/CT imaging showed that the mean whole brain uptake of 18F-JR-1001 in the blocking group was 0.4706, which was lower than that in normal SD rats (1.0561). Additionally, continuous scanning for 60min demonstrated that 18F-JR-1001 exhibited good BBB penetration capability. Conclusion:The synthesized 18F-JR-1001 meets the requirements of production and application, and is proved the potential as a CB1R-targeted tracer in the in vitro experiments, microPET/CT imaging and radioautography.

Objective:To develop and validate a novel PET tracer, N-cyclohexyl-4-((2, 4-dichlorophenyl)(4-(fluoro- 18F)phenyl)methyl)piperazine-1-carboxamide ( 18F-SQKJ-2), targeting cannabinoid type 1 (CB1) receptors for diagnosing psychiatric disorders associated with fear memory. Methods:18F-SQKJ-2 was prepared using a nucleophilic substitution radiochemical synthesis method. For the CB1 receptor blocking experiment, 7 ICR mice were divided into blocking group ( n=4; rimonabant for blocking treatment) and control group 1 ( n=3; no rimonabant blocking treatment). The affinity and specificity of 18F-SQKJ-2 for CB1 receptors were analyzed based on the differences in 18F-SQKJ-2 uptake (percentage injected dose per gram of tissue, %ID/g) by various organs between two groups. The metabolic stability of 18F-SQKJ-2 in vitro was studied using animal tissue homogenates. Ten C57 mice were used to establish fear memory mouse models (fear group, n=6; control group 2, n=4), and the percentage of freezing time was compared between 2 groups. MicroPET scans were used to detect the intracranial distribution of 18F-SQKJ-2, and the relative uptake in each brain region compared to total brain uptake was calculated. Statistical analysis was conducted to compare the differences in CB1 receptor relative total brain uptake in fear-related brain regions between 2 groups. Independent-sample t test and Mann-Whitney U test were used to analyze the data. Results:18F-SQKJ-2 was successfully synthesized with a radiochemical purity ≥98.0% and a corrected radioactive yield of (12.3±6.0)%( n=4). In vitro metabolic stability experiments showed that 18F-SQKJ-2 was basically stable in the liver, blood, and brain within 60min. The CB1 receptor blocking experiment demonstrated that the uptake of 18F-SQKJ-2 in the brains of mice in blocking group was significantly lower than that in control group 1 ((0.95±0.28) vs (3.44±1.16) %ID/g; t=-3.57, P=0.023). The percentage of freezing time in fear group was significantly higher than that in control group 2 (43.28%(39.46%, 52.93%) vs 2.74%(1.52%, 4.85%); Z=-2.45, P=0.010). 18F-SQKJ-2 microPET imaging showed that the uptake of 18F-SQKJ-2 in the cerebral cortex of mice in fear group was significantly increased compared with that in control group 2 ((5.83±0.47)% vs (5.00±0.52)%; t=2.42, P=0.046). Conclusion:18F-SQKJ-2 is successfully prepared with acceptable radiochemical purity and metabolic stability, demonstrating potential for visualizing and quantifying fear memory.

Objectiv To investigate an autosomal dominant non-syndromic hearing loss family pedigree com-prehensively,aiming to precisely define its clinical phenotypes and uncover the underlying molecular genetic etiolo-gy.Methods A detailed interrogation of the proband's medical history and family history was conducted.Physical examinations,audiological assessments and temporal bone CT scans were performed.Genomic DNA was extracted from the peripheral blood of the proband(Ⅳ-8)for whole-exome sequencing(WES).Subsequently,candidate vari-ants identified through WES were validated among family members using Sanger sequencing.Results There were 36 individuals in 4 generations in this family pedigree,showing autosomal dominant inheritance.Among them,16 individuals presented with progressive hearing loss.Audiological examinations were completed for 13 of them,re-vealing normal hearing in three individuals(Ⅲ-1,Ⅲ-1 1,Ⅳ-4)and bilateral symmetric hearing loss of varying se-verity in the remaining ten(Ⅱ-2,Ⅱ-4,Ⅱ-10,Ⅲ-4,Ⅲ-10,Ⅲ-13,Ⅲ-14,Ⅳ-1,Ⅳ-7,Ⅳ-8),and the degree of hearing loss was related to age.WES of Ⅳ-8 revealed that she carried the variant NM_199330.2(HOMER2):c.1064 A＞G(p.Ter354Trpext10),and Sanger sequencing verified the variation at this site.Peripheral blood samples of 18 individuals in this family were collected in total.All affected individuals(Ⅱ-2,Ⅱ-4,Ⅱ-10,Ⅲ-4,Ⅲ-9,Ⅲ-10,Ⅲ-13,Ⅲ-14,Ⅳ-1,Ⅳ-7,Ⅳ-8)carried the HOMER2 c.1064 A＞G variant,except for one young member(Ⅳ-6)who had not yet developed hearing loss.Unaffected individuals(Ⅱ-5,Ⅲ-1,Ⅲ-5,Ⅲ-11,Ⅳ-2,Ⅳ-4)lacked the variant,demonstrating complete cosegregation of genotype and phenotype.According to ACMG guide-lines,this variant was classified as likely pathogenic(PM2+PP1+PM4).Conclusion The c.1064 A＞G(p.Ter354Trpext10)variant of the HOMER2 gene is the molecular genetic etiology of this hereditary deafness family pedigree.

Objective:To prepare ((2-(2-chlorophenyl)-3-(4-((2- 18F-fluoroethyl)oxy)phenyl)-5, 6, 7, 8-tetrahydrooxepino[3, 2-c]pyrazol-8-yl)amino)methanoic acid methyl ester ( 18F-JR-1001) and evaluate its binding affinity to the cannabinoid type 1 receptor (CB1R). Methods:18F-JR-1001 was synthesized using an integrated automated synthesis module, and its radiochemical yield (RCY) and molar activity were determined. Cell-specific uptake, lipid-water partition coefficient (log P), competitive binding assays, and in vitro stability tests were performed. Rimonabant-fed rat models (blocking group) with pre-occupied CB1R were established. Radioautography and microPET/CT imaging were conducted on both the blocking group and normal Sprague-Dawley (SD) rats to evaluate the brain uptake of 18F-JR-1001 and its blood-brain barrier (BBB) penetration capability. Results:The RCY of the synthetic 18F-JR-1001 after decay correction was (32.5±9.2)% ( n=10), with the molar activity of (194.6±67.3)GBq/μmol. Cell experiments demonstrated that 18F-JR-1001 exhibited specificity for CB1R, with log P of 3.40±0.11 ( n=3) and half-maximal inhibitory concentration of 0.975nmol/L. Within 3h at 37℃, the radiochemical purity of 18F-JR-1001 in physiological saline and blood remained above 92%, with no significant radioactive by-product peaks observed. Radioautography showed that the whole brain uptake of 18F-JR-1001 in the blocking group was 65.6% of that in normal SD rats. MicroPET/CT imaging showed that the mean whole brain uptake of 18F-JR-1001 in the blocking group was 0.4706, which was lower than that in normal SD rats (1.0561). Additionally, continuous scanning for 60min demonstrated that 18F-JR-1001 exhibited good BBB penetration capability. Conclusion:The synthesized 18F-JR-1001 meets the requirements of production and application, and is proved the potential as a CB1R-targeted tracer in the in vitro experiments, microPET/CT imaging and radioautography.

Objective:To develop and validate a novel PET tracer, N-cyclohexyl-4-((2, 4-dichlorophenyl)(4-(fluoro- 18F)phenyl)methyl)piperazine-1-carboxamide ( 18F-SQKJ-2), targeting cannabinoid type 1 (CB1) receptors for diagnosing psychiatric disorders associated with fear memory. Methods:18F-SQKJ-2 was prepared using a nucleophilic substitution radiochemical synthesis method. For the CB1 receptor blocking experiment, 7 ICR mice were divided into blocking group ( n=4; rimonabant for blocking treatment) and control group 1 ( n=3; no rimonabant blocking treatment). The affinity and specificity of 18F-SQKJ-2 for CB1 receptors were analyzed based on the differences in 18F-SQKJ-2 uptake (percentage injected dose per gram of tissue, %ID/g) by various organs between two groups. The metabolic stability of 18F-SQKJ-2 in vitro was studied using animal tissue homogenates. Ten C57 mice were used to establish fear memory mouse models (fear group, n=6; control group 2, n=4), and the percentage of freezing time was compared between 2 groups. MicroPET scans were used to detect the intracranial distribution of 18F-SQKJ-2, and the relative uptake in each brain region compared to total brain uptake was calculated. Statistical analysis was conducted to compare the differences in CB1 receptor relative total brain uptake in fear-related brain regions between 2 groups. Independent-sample t test and Mann-Whitney U test were used to analyze the data. Results:18F-SQKJ-2 was successfully synthesized with a radiochemical purity ≥98.0% and a corrected radioactive yield of (12.3±6.0)%( n=4). In vitro metabolic stability experiments showed that 18F-SQKJ-2 was basically stable in the liver, blood, and brain within 60min. The CB1 receptor blocking experiment demonstrated that the uptake of 18F-SQKJ-2 in the brains of mice in blocking group was significantly lower than that in control group 1 ((0.95±0.28) vs (3.44±1.16) %ID/g; t=-3.57, P=0.023). The percentage of freezing time in fear group was significantly higher than that in control group 2 (43.28%(39.46%, 52.93%) vs 2.74%(1.52%, 4.85%); Z=-2.45, P=0.010). 18F-SQKJ-2 microPET imaging showed that the uptake of 18F-SQKJ-2 in the cerebral cortex of mice in fear group was significantly increased compared with that in control group 2 ((5.83±0.47)% vs (5.00±0.52)%; t=2.42, P=0.046). Conclusion:18F-SQKJ-2 is successfully prepared with acceptable radiochemical purity and metabolic stability, demonstrating potential for visualizing and quantifying fear memory.

Secondary osteoporosis is common in patients with early breast cancer, manifesting as low back pain, bone and joint symptoms, and osteoporotic fractures. Bisphosphonate and denosumab can reduce the incidence of fractures by minimizing bone loss, though they differ in efficacy, treatment course, and side effects. Patients should consider the pros and cons when selecting a drug. Recent studies also focus on decreasing the incidence of bone metastases. This article reviews recent advancements in the use of these two drugs for managing bone health in early breast cancer.

Objective:To investigate the correlation between fat distribution and the composite indices of femoral neck strength in obese postmenopausal women.Methods:A total of 293 postmenopausal women with non-low body weight were selected, laboratory tests, body composition analyzer test and double-energy X-ray absorptiometry scan were performed. Based on the body mass index(BMI), they were divided into three groups, the normal BMI group(18.5 kg/m 2≤BMI<24.0 kg/m 2, n=91), the overweight group(24.0 kg/m 2≤BMI<28.0 kg/m 2, n=115), and the obese group(BMI≥28.0 kg/m 2, n=87). The measurement results were analyzed. Results:In the obese group, bone mineral density(BMD) of all sites was higher than that in the normal BMI group and overweight group( P<0.005), compression strength index(CSI), bending strength index(BSI), and impact strength index(ISI) were significantly lower than those in the normal BMI group( P<0.001, P=0.008, P=0.001). In the obese group, waist circumference, waist-hip ratio, total fat mass, appendicular fat mass, and trunk fat mass were risk factors for CSI, BSI and ISI independent of age, fasting blood glucose, and BMI( P<0.05). Visceral fat grade and Chinese visceral adiposity fat index were the risk factors for CSI, BSI, and ISI( P<0.05). Conclusion:The composite indices of femoral neck strength decreased in obese postmenopausal women, and both subcutaneous fat and visceral fat were negatively associated with the composite indices of femoral neck strength.